Krech Maja, Muench Amos, Teichmann Daniel, Kuzman Peter, Suwala Abigail K, Ippen Franziska M, Müther Michael, Weber Katharina J, Wenger-Alakmeh Katharina, Onken Julia, Vajkoczy Peter, Behling Felix, May Sven-Axel, Ntoulias Georgios, Krauss Joachim K, Atallah Oday, Esmaeilzadeh Majid, Mueller Wolf C, Heppner Frank L, Radbruch Helena, Dittmayer Carsten, Stenzel Werner, Koch Arend, Capper David, Kaul David, Paulus Werner, Plate Karl H, Steinbach Joachim P, Czabanka Markus, Beschorner Rudi, von Deimling Andreas, Bockmayr Michael, Neumann Julia E, Brandner Sebastian, Krieger Teresa, Hartmann Christian, Thomas Christian, Schweizer Leonille
Department of Neuropathology, Charité - Universitätsmedizin Berlin, corporate member of, Freie Universität Berlin and Humboldt-Universität Zu Berlin, Berlin, Germany.
Institute of Pathology, Charité - Universitätsmedizin Berlin, corporate member of, Freie Universität Berlin and Humboldt-Universität Zu Berlin, Berlin, Germany.
Acta Neuropathol. 2025 Jun 11;149(1):61. doi: 10.1007/s00401-025-02894-3.
Central neurocytomas (CN) are intraventricular brain tumors predominantly occurring in young adults. Although prognosis is usually favorable, tumor recurrence is common, particularly following subtotal resection (STR). Currently, the risk of progression is evaluated using atypical features and an elevated Ki67 proliferation index. However, these markers lack consistent definitions, raising the need for objective criteria. Genome-wide DNA methylation profiles were examined in 136 tumors histologically classified as CN. Clinical/histopathological characteristics were assessed in 93/90 cases, and whole-exome sequencing was conducted in 12 cases. Clinical and molecular characteristics were integrated into a survival model to predict progression-free survival (PFS). A diagnosis of CN was epigenetically confirmed in 125 of 136 cases (92%). No DNA methylation subgroups were identified, but global DNA hypomethylation emerged as a hallmark feature of CN associated with higher recurrence risk. Risk stratification based on histological features of atypia and Ki67 proliferation index was not reproducible across neuropathologists. Hypomethylation at the FGFR3 locus, accompanied by increased FGFR3 protein expression, was observed in 97% of cases. Gross total resection was associated with significantly improved PFS compared to STR, while patients undergoing STR receiving radiotherapy had a better outcome (p = 0.0001). Younger patients were identified as having a higher risk of recurrence (p = 0.026). Patient age and treatment strategy were key factors associated with survival outcomes in this cohort. These findings underscore the importance of closer follow-up for younger patients and radiotherapy for STR cases. Furthermore, FGFR3 represents a hallmark feature and potential therapeutic target, warranting further investigation.
中枢神经细胞瘤（CN）是主要发生于年轻人的脑室内肿瘤。尽管预后通常良好，但肿瘤复发很常见，尤其是在次全切除术后（STR）。目前，使用非典型特征和升高的Ki67增殖指数来评估进展风险。然而，这些标志物缺乏一致的定义，因此需要客观标准。对136例组织学分类为CN的肿瘤进行了全基因组DNA甲基化谱分析。对93/90例病例评估了临床/组织病理学特征，并对12例病例进行了全外显子组测序。将临床和分子特征整合到生存模型中以预测无进展生存期（PFS）。136例病例中有125例（92%）通过表观遗传学方法确诊为CN。未发现DNA甲基化亚组，但整体DNA低甲基化成为与较高复发风险相关的CN的标志性特征。基于非典型性组织学特征和Ki67增殖指数的风险分层在神经病理学家之间不可重复。在97%的病例中观察到FGFR3基因座低甲基化，同时伴有FGFR3蛋白表达增加。与STR相比，全切除与显著改善的PFS相关，而接受STR的患者接受放疗后预后更好（p = 0.0001）。年轻患者被确定为复发风险较高（p = 0.026）。患者年龄和治疗策略是该队列中与生存结果相关的关键因素。这些发现强调了对年轻患者进行密切随访以及对STR病例进行放疗的重要性。此外，FGFR3是一个标志性特征和潜在的治疗靶点，值得进一步研究。
